1. Technical Field of the Invention
The present invention relates to compositions for topical application, to processes for preparing such compositions and to applications thereof as cosmetic or pharmaceutical products, the compositions being particularly useful for treating acne.
2. Description of Background and/or Related and/or Prior Art
Acne is a common multi-factor pathology that attacks skin rich in sebaceous glands (face, shoulder area, arms and intertriginous areas). It is the most commonly occurring form of dermatosis. The following five pathogenic factors play a determining role in the development of acne:
1. genetic predisposition;
2. overproduction of sebum (seborrhoea);
3. androgens;
4. follicular keratinization disorders (comedogenesis); and
5. bacterial colonization and inflammatory factors.
There are several forms of acne, the common factor of all of them being attack of the pilosebaceous follicles. Exemplary are acne conglobata, acne keloid on the nape of the neck, acne medicamentosa, recurrent miliary acne, acne necrotica, acne neonatorum, premenstrual acne, occupational acne, acne rosacea, senile acne, solar acne and acne vulgaris.
Acne vulgaris, also known as polymorphous juvenile acne, is the most common. It comprises four stages, but it is not necessary to pass through all the stages:
Stage 1 corresponds to comedonal acne, characterized by a large number of open and/or closed comedones and of microcysts.
Stage 2, or papulopustular acne, is of mild to moderate seriousness. It is characterized by the presence of open and/or closed comedones and microcysts, but also of red papules and of pustules. It mainly affects the face and leaves few scars.
Stage 3, or papulocomedonal acne, is more serious and extends to the back, the thorax and the shoulders. It is accompanied by a larger number of scars.
Stage 4, or nodulocystic acne, is accompanied by numerous scars. It exhibits nodules and also has large painful purplish pustules.
The various forms of acne described above can be treated with active agents, such as antiseborrhoeics and antiinfectives, for example benzoyl peroxide (in particular, the product Eclaran® marketed by Pierre Fabre), with retinoids, such as tretinoin (in particular, the product Retacnyl® marketed by Galderma) or isotretinoin (the product Roaccutane® marketed by Laboratoires Roche), or with naphthoic acid compounds. Naphthoic acid compounds, such as, in particular, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, commonly known as adapalene (the product Differine® marketed by Galderma), are widely described and recognized as active ingredients which are as effective as tretinoin in the treatment of acne.
The combination of several local treatments (antibiotics, retinoids, peroxides, zinc) is also used in dermatology to increase the efficacy of the active ingredients and to reduce their toxicity (Cunliffe W. J., J. Dermatol. Treat., 2000, 11 (suppl. 2), S13-S14) but the multiple application of various dermatological products can be quite laborious and demanding for the patient.
The advantage of providing a new treatment which is effective under dermatological conditions, in a stable composition offering good cosmeticity, and which can be applied just once and is pleasant for the patient to use, is therefore apparent.
Among this panoply of therapeutics proposed to those skilled in the art, none would encourage one to combine, in the same composition, benzoyl peroxide and a retinoid.
However, the formulation of such a composition presents several problems.
First, the efficacy of benzoyl peroxide is linked to its decomposition when it is brought into contact with the skin. In fact, it is the oxidizing properties of the free radicals produced during this decomposition which result in the desired effect. Thus, to maintain optimum efficacy of the benzoyl peroxide, it is important to prevent it from decomposing before use, i.e., during storage.
However, benzoyl peroxide is an unstable chemical compound, which makes it difficult to formulate it into final products.
The solubility and stability of benzoyl peroxide have been studied by Chellquist et al. in ethanol, propylene glycol and various mixtures of polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. and Gorman W. G., Pharm. Res., 1992, Vol. 9: 1341-1346).
This prior art specifies, moreover, that the stability of benzoyl peroxide is greatly influenced by the chemical composition of the formulation and by the storage temperature thereof. Benzoyl peroxide is extremely reactive and degrades in solution at low temperature due to the instability of its peroxide bond.
The authors thus note that benzoyl peroxide in solution degrades more or less rapidly in all of the solvents studied, depending on the type of solvent and on the concentration thereof.
The degradation times of benzoyl peroxide in PEG 400 (0.5 mg/g), in ethanol and in propylene glycol are, respectively, 1.4, 29 and 53 days at 40° C.
Such a degradation does not make it possible to formulate a product intended for sale.
Another difficulty to be overcome in the formulation of a composition comprising both benzoyl peroxide and a retinoid is that most retinoids are particularly sensitive to natural oxidation, to visible light and to ultraviolet radiation, and since benzoyl peroxide is a strong oxidizing agent, the chemical compatibility of these compounds in the same formulation poses numerous problems of stability from the physical and chemical point of view.
A study of the stability of two retinoids was carried out by combining two commercially available products, one containing a retinoid (tretinoin or adapalene) and the second being benzoyl peroxide-based (B. Martin et al., Br. J. Dermatol. (1998) 139 (suppl. 52), 8-11).
The presence of the benzoyl peroxide-based formulation causes very rapid degradation of the oxidation-sensitive retinoids: it is measured that 50% of the tretinoin degrades in 2 hours, and 95% in 24 hours. In the composition in which the retinoid is adapalene, no degradation of the adapalene was measured for 24 hours. This study confirms that benzoyl peroxide is degraded and degrades oxidation-sensitive retinoids over time, gradually releasing benzoic acid into final products.
However, it is apparent that the degradation of benzoyl peroxide and of retinoids is undesirable since it is detrimental to the effectiveness of the composition containing them.
Nothing would prompt the combination of these two active agents to obtain a stable composition, given that it was customarily known that the presence of benzoyl peroxide chemically and physically destabilized this type of composition.
Furthermore, those skilled in the art are constantly seeking to improve the efficacy and tolerance of compositions containing benzoyl peroxide and a naphthoic acid compound. One of the solutions for improving the efficacy is to increase the amounts of active agents present in the composition or to increase the treatment times. Such modifications generally result in an increase in the induced irritation. For this reason, it is necessary to provide compositions that can further improve the tolerance of the active ingredients.